1. Field of the Invention
The present invention relates generally to the production of 1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane), which is widely used around the world as an inhalation anesthetic.
2. Description of Related Art
There are several known methods for the production of sevoflurane, particularly by the reaction of formaldehyde (or a formaldehyde equivalent), hydrogen fluoride (HF), and hexafluoroisopropanol (HFIP). U.S. Pat. No. 4,250,334 describes a process in which HFIP is added to a mixture of a stoichiometric excess of paraformaldehyde and HF plus sufficient sulfuric acid to sequester most of the water formed in the reaction. WO 97/25303 describes a process for the production of sevoflurane in which essentially pure bis(fluoromethyl)ether (BFME) is allowed to react with HFIP and sulfuric acid. U.S. Pat. No. 6,469,219 describes a process in which HFIP and a formaldehyde equivalent are allowed to react with excess HF under distillative or extractive conditions in order to produce sevoflurane.
In all of these processes, unreacted HFIP may remain in the product mixture, as well as BFME, methyl hexafluoroisopropyl ether (MHFIP), polyethers containing the HFIP and formaldehyde moieties, and various other undesired species. These impurities must be removed from the crude sevoflurane product in order to obtain a pharmaceutically acceptable form of the material. Many of these impurities can be removed by distillation, but HFIP is difficult to separate from sevoflurane since they have similar boiling points and may distill as an azeotrope. Simple washing of the crude sevoflurane product with water has been found to be inefficient, time consuming, and costly.
WO 99/44978 describes a process for the removal of HFIP from sevoflurane by performing aqueous base washes of a crude sevoflurane product. This process requires meticulous control of the amount of base used in proportion to the amount of HFIP present, as well as careful temperature control in order to avoid the conversion of some of the sevoflurane to compound A, a highly toxic and undesired side product. Also, prolonged processing is required with repeated sampling and analysis, in order to ensure adequate removal of HFIP without forming too much compound A. Thus, this approach adds an unattractive amount of cost and complexity to the production process.
WO02/50005 and related US 2004/0124076 describe a process for purifying a crude sevoflurane product by contacting a crude composition of sevoflurane and HFIP with a modifier to decrease the vapor pressure of the ether and/or alcohol, preferably by decreasing the vapor pressure of HFIP. The ether and alcohol then may be separated by distillation. The modifier typically is an amine or some other group that is capable of bonding with HFIP, or at least donating electrons to the alcohol. The use of such a modifier adds cost and complexity to the production process since it must be completely removed from both the sevoflurane product, as well as the unreacted HFIP that is recycled back into the reaction phase. The modifier then must either be recycled or isolated for disposal. Odor issues are also of concern when amines or thiols are used as the modifier.
Addition of alkali metal salts to the distillation of sevoflurane is described in U.S. Pat. No. 5,684,211 as a method to suppress the decomposition, which forms Compound A. The patent does not speak to hexafluoroisopropanol, azeotropes of it or methods of its removal by distillation.
Middleton and Lindsey in the Journal of the American Chemical Society, 1964, 86: 4948-4952 have described azeotropes of fluorinated secondary alcohols such as hexafluoroisopropanol in which the normal boiling point is higher than the alcohol. Methods of breaking these azeotropes were also described, but applications of these azeotropes were not described.
Other proposed methods of sevoflurane synthesis, such as that described in U.S. Pat. No. 6,100,434, avoid this difficult sevoflurane/hexafluoroisopropanol separation by using more complicated synthetic strategies.
What is still needed is a distillative method for the efficient separation of sevoflurane and hexafluoroisopropanol.